Hypomethylated T cells aberrantly overexpressing the methylation sensitive genes CD11a, IFN-gamma, perform and CD70 have been implicated in the pathogenesis of human lupus. Recent studies from this group demonstrate that KIR genes, implicated in acute coronary syndromes (unstable angina and myocardial infarctions), are also methylation sensitive and overexpressed on lupus T cells. Preliminary studies suggest that methylation sensitive T cell gene expression can be increased by restricting either folate or Met, or by decreasing DNA methyl transferase (DNMT) enzyme activity with direct/specific inhibitors, signaling inhibitors, or SAH, and that these effects are additive. Further, supplementation with either Met or folate decreases or prevents overexpression of the methylation sensitive genes by these inhibitors. These results suggest that decreases in DNMT expression due to environmental xenobiotics affecting transferase levels or function, together with dietary influences, are additive in affecting methylation sensitive gene expression, and ultimately causal in the development of lupus and its complications. These results also suggest that dietary supplementation of one or more nutrients involved in DNA methylation may be protective. These hypotheses will be tested by comparing the effects of: 1) nutrient restriction/supplementation and DNA methylation inhibitors alone and in combination on the expression and methylation of T cell CD11a, CD70, IFN-gamma, perforin and KIR and determining the consequences on cytotoxicity for macrophages and endothelial cells, 2) nutrient restriction and supplementation in vitro on the expression and methylation of methylation sensitive genes in T cells from subjects with lupus and normal controls, and 3) control, methyl-donor deficient, and methyl-rich diet on the expression of methylation sensitive T cell genes and lupus severity in mice with autoimmunity caused by an inducible ERK pathway signaling defect. Evidence that dietary modification can ameliorate aberrant gene expression in vitro and disease severity in the murine model will lead to studies extending these results to lupus patients.